Apparatus for performng an extracorporeal blood treatment

ABSTRACT

An extracorporeal blood treatment apparatus is provided comprising a filtration unit ( 2 ) connected to a blood circuit ( 17 ) and to a dialysate circuit ( 32 ); a control unit ( 12 ) is configured for calculating a sodium concentration value for the blood; the estimation of the sodium concentration includes the sub-step of calculating the sodium concentration value as an algebraic sum of a main contribution term based on the isoconductive sodium concentrate and of an offset contribution term based on a concentration of at least a substance in the dialysis fluid chosen in the group including bicarbonate, potassium, acetate, lactate, citrate, magnesium, calcium, sulphate and phosphate.

TECHNICAL FIELD

The present invention relates to an apparatus for extracorporeal bloodtreatment and a method for estimating a blood parameter in anextracorporeal blood treatment apparatus.

In particular, the invention may allow determining a blood parameter(e.g. plasma sodium) during a hemodialysis or hemodiafiltrationtreatment through post-dialyzer conductivity measurements.

BACKGROUND OF THE INVENTION

The kidneys fulfil many functions, including the removal of water, theexcretion of catabolites (or waste from the metabolism, for example ureaand creatinine), the regulation of the concentration of the electrolytesin the blood (e.g. sodium, potassium, magnesium, calcium, bicarbonates,phosphates, chlorides) and the regulation of the acid/base equilibriumwithin the body, which is obtained in particular by the removal of weakacids and by the production of ammonium salts.

In individuals who have lost the use of their kidneys, since theseexcretion and regulation mechanisms no longer work, the body accumulateswater and waste from the metabolism and exhibits an excess ofelectrolytes, as well as, in general, acidosis, the pH of the bloodplasma shifting downwards, below 7.35 (the blood pH normally varieswithin narrow limits of between 7.35 and 7.45).

In order to overcome renal dysfunction, resort is conventionally made toa blood treatment involving extracorporeal circulation through anexchanger having a semipermeable membrane (dialyzer) in which thepatient's blood is circulated on one side of the membrane and a dialysisliquid, comprising the main electrolytes of the blood in concentrationsclose to those in the blood of a healthy subject, is circulated on theother side.

Furthermore, a pressure difference is created between the twocompartments of the dialyzer which are delimited by the semipermeablemembrane, so that a fraction of the plasma fluid passes byultrafiltration through the membrane into the compartment containing thedialysis liquid.

The blood treatment which takes place in a dialyzer as regards wastefrom the metabolism and electrolytes results from two mechanisms ofmolecular transport through the membrane.

On the one hand, the molecules migrate from the liquid where theirconcentration is higher to the liquid where their concentration islower. This is diffusive transport.

On the other hand, certain catabolites and certain electrolytes areentrained by the plasma fluid which filters through the membrane underthe effect of the pressure difference created between the twocompartments of the exchanger. This is convective transport.

Three of the abovementioned functions of the kidney, namely the removalof water, the excretion of catabolites and the regulation of theelectrolytic concentration of the blood, are therefore performed in aconventional blood treatment device by the combination of dialysis andblood filtration (this combination is referred to as hemodialysis).

Some known dialysis machines offer options for both ultrafiltration andsodium profiling with an attempt to improve tolerance forultrafiltration as dialysis session time became shorter. Indeed reduceddialysis time is associated to an increase in patient intolerance forthe consequent higher UF rate.

In simple terms, the UF rate is varied so to favor improved vascularrefilling. Moreover, the sodium content of the dialysis fluid is variedduring the course of the treatment to directly influence plasma sodiumlevels. The intent is to control the rate at which sodium leaves thebloodstream into the dialysate.

There can be negative consequences to a high dialysate sodiumconcentration. Sodium can accumulate in the patient leading to anincreased post-dialysis thirst, increased interdialytic weight gain andthe development of hypertension. Sodium profiling was developed toachieve the benefits of high plasma sodium levels while at the same timeavoiding unnecessary high intradialytic sodium uptake by the patientwith the associated risk of sodium loading. The idea is to minimizeintradialytic side-effects while removing the amount of sodium necessaryto avoid sodium overload.

A normal sodium value post dialysis can be reached for hyper- orhyponatremic patients. However, monitoring of the patient's clinicalstatus will indicate if post dialysis normonatremia is indicated. Forexample, hypernatremic patients often stabilize at a sodium level thatis higher than the post dialysis level and may suffer side effects ifhyponatremic dialysis is conducted with the intention of lowering theirsodium levels.

In the above described situation a need to properly estimate and tocontinuously know and control the plasma sodium arises.

It is known from document U.S. Pat. No. 5,100,554 to Polaschegg a methodfor the in-vivo determination of hemodialysis parameters. To carry outhemodialysis with the greatest efficiency and safety, it is necessary toknow the dialysis dose which depends on the clearance of the filtrationunit. To be able to determine the same in vivo, the invention provides amethod in which the electrolyte transfer of the dialysis fluid ismeasured by means of a conductivity meter at two different predetermineddialysis fluid ion concentrations and both the dialysance and plasmaconductivity are determined on the basis thereof.

Document EP547025 to Sternby teaches a method for determining aconcentration of sodium in the blood of a patient undergoing a dialysistreatment in an artificial kidney and/or the actual dialysance forsodium of the artificial kidney. The artificial kidney comprises anextracorporeal blood circuit connected to a filtration unit with asemipermeable membrane delimiting a first compartment for thecirculation of blood on one side of the membrane and a secondcompartment for circulating the dialysis fluid; the method includes thesteps of circulating successively in the second compartment of thefiltration unit a first and a second dialysis liquid having differentconcentrations of sodium, measuring in the first and second dialysisliquids the conductivity upstream and downstream of the filtration unit,and calculating from the measured conductivity in the first and seconddialysis fluids, the conductivity of the blood at the inlet of thefiltration unit and/or the actual dialysance of the artificial kidney.

In particular, the conductivity of the blood and the actual dialysanceis calculated according to the formula:

κ_(d out)=κ_(d in)(κ_(b)−κ_(d in))×D/Q _(d)

whereinκ_(d in) conductivity of the dialysis liquid upstream of the filtrationunit;κ_(d out)=conductivity of the dialysis liquid downstream of thefiltration unit;κ_(b in)=conductivity of the blood upstream of the filtration unit;D=dialysance of the artificial kidney for conductivity;Q_(d)=flow rate of the dialysis liquid.

EP658352, EP920877, and EP1108438 describe further improvements of theabove described method for plasma conductivity calculation.

The basic principle of the above described monitoring systems is thecontinuous measurement of the outlet dialysate conductivity when theinlet dialysate conductivity is changed for about 1 mS/cm during twominutes. This measurement can be programmed to take place every e.g. 15,30, 45 or 60 minutes.

The mathematical outlet conductivity modeling allows the calculation oftwo dialysis process parameters, namely plasma conductivity andeffective ionic dialysance or ionic clearance

Plasma conductivity is the reflection of the amount of electrolytes,such as sodium and other physiologically acceptable ions, in thepatient. This enables to determine if patients will leave the clinicoverloaded with sodium.

Notwithstanding the use of the above identified methods is today largelyspread, there are still outstanding problems to give the blood propertyresult a physiological meaning.

Strictly the “plasma conductivity” not only measure an unambiguous bloodproperty but it is strongly influenced by the measurement itself.Generally it is assumed that if the conductivity in fluid entering thefiltration unit is equal to the conductivity leaving the filtration unitwill represent an unambiguous blood property.

However this is an approximation and it is almost impossible to verifycorrectness of the calculation by taking and measuring samples of theblood. In the past, there have been attempts to statistically connectplasma conductivity to plasma sodium, but the spread in data is large.

SUMMARY

An aim of the present invention is providing an extracorporeal bloodtreatment apparatus capable to properly estimate a blood parameter inthe extracorporeal blood.

In detail it is an aim of the present invention to provide anextracorporeal blood treatment apparatus with a proper tool forestimating a concentration of at least a substance in the blood or aconcentration-related parameter of at least a substance in the blood

A further aim of the invention is to make available an extracorporealblood treatment apparatus provided with a simple model of the iontransports in the filtration unit that contribute to conductivitychange. The mathematical model allows the calculation of the plasmasodium from the conductivity measurements once known or estimated theblood values of some electrolytes.

It is an auxiliary aim of the invention to provide an extracorporealblood treatment machine configured to automatically perform a properautomatic setting of the dialysis fluid conductivity based on thedetermined blood parameter.

A further auxiliary aim of the invention is to make available a dialysisapparatus able to provide an automated delivery and control of thedialysis prescription, particularly in order to restore at each dialysissession the proper sodium-water equilibrium to the patient.

At least one of the above-indicated aims is attained by an apparatus anda corresponding method as in one or more of the appended claims, takensingly or in any combination.

According to a first independent aspect of the invention anextracorporeal blood treatment apparatus is provided including:

-   -   a filtration unit (2) having a primary chamber (3) and a        secondary chamber (4) separated by a semi-permeable membrane        (5);    -   a blood withdrawal line (6) connected to an inlet of the primary        chamber (3),    -   a blood return line (7) connected to an outlet of the primary        chamber (3), said blood lines being configured for connection to        a patient cardiovascular system;    -   a dialysis supply line (8), optionally connected to an inlet of        the secondary chamber (4) for circulating a dialysis fluid;    -   a dialysis effluent line (13) connected to an outlet of the        secondary chamber (4);    -   a control unit (12) programmed for receiving a value of a first        parameter representative of an isoconductive dialysis, the first        parameter being chosen in the group including a concentration of        at least a substance, a concentration related parameter of at        least a substance, a conductivity or a conductivity related        parameter, wherein said control unit (12) is configured for:    -   calculating the value of a second parameter, said second        parameter being chosen in a group including a concentration of        at least a substance in the blood and a concentration-related        parameter of at least a substance in the blood; wherein the step        of calculating the value of the second parameter is performed as        a function of a main contribution term based on the first        parameter and as a function of an offset contribution term based        on a concentration of at least a substance in the dialysis fluid        chosen in the group including bicarbonate, potassium, acetate,        lactate, citrate, magnesium, calcium, sulphate, and phosphate;        and optionally,    -   storing said parameter value in a memory (46) connected to the        control unit (12).

In a further independent aspect, an apparatus for extracorporeal bloodtreatment is provided comprising:

-   -   a filtration unit (2) having a primary chamber (3) and a        secondary chamber (4) separated by a semi-permeable membrane        (5);    -   a blood withdrawal line (6) connected to an inlet of the primary        chamber (3),    -   a blood return line (7) connected to an outlet of the primary        chamber (3), said blood lines being configured for connection to        a patient cardiovascular system;    -   a dialysis effluent line (13) connected to an outlet of the        secondary chamber (4);    -   a control unit (12) programmed for receiving a value of a first        parameter representative of an isoconductive dialysis, the first        parameter being chosen in the group including a concentration of        at least a substance, a concentration related parameter of at        least a substance, a conductivity or a conductivity related        parameter, wherein said control unit (12) is configured for:    -   calculating the value of a second parameter of the blood, said        second parameter being chosen in a group including a        concentration of at least a substance in the blood and a        concentration-related parameter of at least a substance in the        blood; wherein the calculating the parameter value is performed        as a function of a main contribution term based on the first        parameter and as a function of an offset contribution term based        on a concentration of at least a substance in the blood chosen        in the group including bicarbonate, potassium, acetate, lactate,        citrate, magnesium, calcium, sulphate, and phosphate; and        optionally,    -   storing said second parameter value in a memory (46) connected        to the control unit (12), in particular the parameter value        being the plasma sodium concentration.

In a further independent aspect a method for estimating a bloodparameter in an apparatus for extracorporeal blood treatment isprovided, the apparatus comprising:

-   -   a filtration unit (2) having a primary chamber (3) and a        secondary chamber (4) separated by a semi-permeable membrane        (5);    -   a blood withdrawal line (6) connected to an inlet of the primary        chamber (3),    -   a blood return line (7) connected to an outlet of the primary        chamber (3), said blood lines being configured for connection to        a patient cardiovascular system;    -   a dialysis supply line (8), optionally connected to an inlet of        the secondary chamber (4) for circulating a dialysis fluid;    -   a dialysis effluent line (13) connected to an outlet of the        secondary chamber (4);    -   a control unit (12) programmed for receiving a value of a first        parameter representative of an isoconductive dialysis, the first        parameter being chosen in the group including a concentration of        at least a substance, a concentration related parameter of at        least a substance, a conductivity or a conductivity related        parameter, the method comprising the following steps performed        by the control unit:    -   calculating the value of a second parameter of the blood, said        second parameter being chosen in a group including a        concentration of at least a substance in the blood and a        concentration-related parameter of at least a substance in the        blood; wherein the step of calculating the value of the second        parameter is performed as a function of a main contribution term        based on the first parameter and as a function of an offset        contribution term based on a difference, in particular a        weighted difference, in concentration of at least a substance in        the dialysis fluid and the same substance in the blood plasma;        and optionally,    -   storing said second parameter value in a memory (46) connected        to the control unit (12).

In a 2^(nd) aspect according to the previous aspects, the control unitis configured to calculate the offset contribution term based on theconcentration of two or more substances in the dialysis fluid chosen inthe group including bicarbonate, potassium, acetate, lactate, citrate,magnesium, calcium, sulphate, and phosphate, in particular as a functionof the concentration of at least three of said substances, optionally asa function of the concentration of bicarbonate, potassium, acetate, andcitrate in the dialysis fluid.

In a 3^(rd) aspect according to the previous aspects, the control unitis configured to calculate the offset contribution term as a function ofthe difference, in particular a weighted difference, in concentration ofat least a substance in the dialysis fluid and the same substance in theblood plasma.

In a 4^(th) aspect according to the previous aspects, the control unitis configured to calculate the offset contribution term as a function ofthe difference, in particular a weighted difference, in concentration ofat least a substance in the dialysis fluid and the same substance in theplasma, said substance being chosen in the group including bicarbonate,potassium, acetate, lactate, and citrate, in particular as a function ofthe difference, in particular a weighted difference, in concentration ofat least two of said substances, optionally as a function of thedifference, in particular a weighted difference, in concentration ofbicarbonate, potassium, and acetate in the dialysis fluid and plasma,even more optionally as a function of the difference, in particular aweighted difference, in concentration of bicarbonate, potassium,citrate, and acetate in the dialysis fluid and plasma.

In a 5^(th) aspect according to the previous aspects, the valuerepresentative of the isoconductive dialysis is chosen in the groupincluding a concentration of at least a substance in the dialysis fluid,a concentration related parameter of at least a substance in thedialysis fluid, a dialysis fluid conductivity, a dialysis fluidconductivity related parameter, a plasma conductivity or a plasmaconductivity related parameter, in particular the first parameter is anisoconductive sodium concentration or an isoconductive sodiumconcentration-related parameter.

In a 6^(th) aspect according to the previous aspects, the secondparameter is the concentration of at least a substance in the blood,said substance being in particular sodium.

In a 7^(th) aspect according to the previous aspects, the firstparameter is the isoconductive sodium concentration and the secondparameter is the sodium concentration in the blood.

In a 8^(th) aspect according to the previous aspects, the maincontribution term is dimensionally a concentration of a substance in afluid.

In a 9^(th) aspect according to the previous aspect, the maincontribution term is a concentration value which if used as a dialysisfluid concentration of sodium would run an isoconductive dialysis.

In a 10^(th) aspect according to the previous aspects, the maincontribution term affects the second parameter for at least 80% of thesecond parameter value, the offset contribution term contributes to thesecond parameter for less than 20% of the second parameter value.

In a 11^(th) aspect according to the previous aspects, the sub-step ofcalculating the second parameter value as a function of the maincontribution term and the offset contribution term is a sub-step ofcalculating an algebraic sum, particularly a weighted algebraic sum, ofat least the main contribution term and the offset contribution term andparticularly wherein the offset contribution term is dimensionally aconcentration of a substance in a fluid.

In a 12^(th) aspect according to the previous aspects, the maincontribution term affects the second parameter for at least 90% of thesecond parameter value, the offset contribution term contributing to thesecond parameter for less than 10% of the second parameter value.

In a 13^(th) aspect according to the previous aspects, the apparatusincludes a preparation device (9) for preparing a dialysis fluidconnected to said supply line (8) and comprising regulating means (10)for regulating the composition of the dialysis fluid, the regulatingmeans (10) being connected to the control unit (12).

In a 14th aspect according to the previous aspect, the control unit (12)is configured for setting a third parameter value for the dialysis fluidin the dialysis supply line (8) at a set point, said third parameter ofthe dialysis fluid being at least one chosen in a group including aconductivity of the dialysis fluid, a conductivity-related parameter ofthe dialysis fluid, a concentration of at least a substance in thedialysis fluid and a concentration-related parameter of at least asubstance in the dialysis fluid.

In a 15^(th) aspect according to the previous 13^(th) aspect, thecontrol unit (12) is configured for determining a profile in time for athird parameter value for the dialysis fluid in the dialysis supply line(8), said third parameter of the dialysis fluid being at least onechosen in a group including a conductivity of the dialysis fluid, aconductivity-related parameter of the dialysis fluid, a concentration ofat least a substance in the dialysis fluid and a concentration-relatedparameter of at least a substance in the dialysis fluid; wherein thecontrol unit drives the regulating means (10) for regulating theconductivity or the concentration of at least a substance in thedialysis fluid, the profile in time for the third parameter being basedon the second parameter.

In a 16^(th) aspect according to anyone of the previous aspects, thecontrol unit drives regulating means (10) for regulating theconductivity or the concentration of at least a substance in thedialysis fluid.

In a 17^(th) aspect according to the previous four aspects, the controlunit setting the third parameter value for the dialysis fluid in thedialysis supply line (8) at the set point which is based on the secondparameter.

In a 18^(th) aspect according to the previous aspect, the regulatingmeans (10) regulates the concentration of at least a substance in thedialysis fluid, in particular a ionic substance, such as sodium.

In a 19^(th) aspect according to the previous aspect, the control unitdrives the regulating means (10) for regulating the sodium concentrationin the dialysis fluid to set the parameter value for the dialysis fluidin the dialysis supply line (8) at the calculated second parametervalue.

In a 20^(th) aspect according to anyone of the previous aspects, thecontrol unit is configured to calculate the offset contribution term asa function of the molar conductivities of at least a substance in thedialysis fluid chosen in the group including sodium bicarbonate(NaHCO₃), sodium chloride (NaCl), sodium acetate (NaCH₃COO), potassiumchloride (KCl), sodium lactate (NaC₃H₅O₃), and trisodium citrate(Na₃C₆H₅O₇), in particular as a function of the molar conductivities ofat least two of said substances, in more detail as a function of themolar conductivities of at least three of said substances, optionally asa function of the molar conductivities of at least three substanceschosen in the group including sodium bicarbonate (NaHCO₃), sodiumchloride (NaCl), sodium acetate (NaCH₃COO), trisodium citrate(Na₃C₆H₅O₇), and potassium chloride (KCl).

In a 21^(st) aspect according to anyone of the previous aspects, thecontrol unit is configured to calculate the offset contribution term asa function of a difference between two molar conductivities.

In a 22^(nd) aspect according to anyone of the previous aspects, thecontrol unit is configured to calculate the offset contribution term asa function of a difference between a first molar conductivity of asubstance chosen in the group including sodium bicarbonate (NaHCO₃),sodium acetate (NaCH₃COO), trisodium citrate (Na₃C₆H₅O₇), sodium lactate(NaC₃H₅O₃), potassium chloride (KCl), and a molar conductivity of sodiumchloride (NaCl).

In a 23^(rd) aspect according to anyone of the previous aspects, thecontrol unit is configured to calculate the offset contribution term asa function of a difference between a molar conductivity of sodiumbicarbonate (NaHCO₃), and a molar conductivity of sodium chloride(NaCl).

In a 24^(th) aspect according to anyone of the previous aspects, thecontrol unit is configured to calculate the offset contribution term asa function of a difference between a molar conductivity of sodiumacetate (NaCH₃COO), and a molar conductivity of sodium chloride (NaCl).

In a 25^(th) aspect according to anyone of the previous aspects, thecontrol unit is configured to calculate the offset contribution term asa function of a molar conductivity of potassium chloride (KCl).

In a 26^(th) aspect according to the previous aspects, the control unitis configured to calculate the offset contribution term as a function ofan estimated or measured plasma water concentration of at least asubstance chosen in the group including bicarbonate, potassium, acetate,lactate, and citrate, in particular as a function of the estimated ormeasured plasma water concentration of at least two of said substances,in more detail as a function of the estimated plasma water concentrationof at least three of said substances, optionally as a function of theestimated plasma water concentration of bicarbonate, potassium, citrate,and acetate.

In a 27^(th) aspect according to the previous aspect, the estimatedplasma water concentration of at least a substance chosen in the groupincluding bicarbonate, potassium, citrate, and acetate is the meanpre-dialysis values of the corresponding substance for large patientpopulations or historical data of the corresponding substance for theindividual patient or theoretical values of the corresponding substanceor measured values of the corresponding substance.

In a 28^(th) aspect according to the previous aspects 26^(th) and27^(th), the estimated plasma water concentration is adjusted by arespective fixed adjusting factor taking account of the Donnan effect.

In a 29^(th) aspect according to the previous aspects, the control unitis configured to calculate the offset contribution term as an algebraicsum of at least two components, a first component being function of thedifference, in particular a weighted difference, in concentration of atleast a substance in the dialysis fluid and the same substance in theblood plasma, the second component being function of the difference, inparticular a weighted difference, in concentration of at least a secondsubstance in the dialysis fluid and the same second substance in theblood plasma.

In a 30^(th) aspect according to the previous aspects, the control unitis configured to calculate the offset contribution term as an algebraicsum of at least three components, a first component being function ofthe difference, in particular a weighted difference, in concentration ofat least a substance in the dialysis fluid and the same substance in theblood plasma, the second component being function of the difference, inparticular a weighted difference, in concentration of at least a secondsubstance in the dialysis fluid and the same second substance in theblood plasma, the third component being function of the difference, inparticular a weighted difference, in concentration of at least a thirdsubstance in the dialysis fluid and the same third substance in theblood plasma, optionally a fourth component being function of thedifference, in particular a weighted difference, in concentration of atleast a fourth substance in the dialysis fluid and the same fourthsubstance in the blood plasma.

In a 31^(st) aspect according to the previous aspects, the control unitis configured to calculate the offset contribution term as an algebraicsum of at least two components, a first component being function of aconcentration of at least a substance in the dialysis fluid and/or inthe blood plasma, a second component being function of a concentrationof at least a second substance in the dialysis fluid and/or in the bloodplasma.

In a 32^(nd) aspect according to the previous aspects, the control unitis configured to calculate the offset contribution term as an algebraicsum of at least three components, a first component being function of aconcentration of at least a substance in the dialysis fluid and/or inthe blood plasma, a second component being function of a concentrationof at least a second substance in the dialysis fluid and/or in the bloodplasma, a third component being function of a concentration of at leasta third substance in the dialysis fluid and/or in the blood plasma,optionally a fourth component being function of a concentration of atleast a fourth substance in the dialysis fluid and/or in the bloodplasma.

In a 33^(rd) aspect according to the previous aspects 29^(th) to32^(nd), said substance is an ion chosen in the group includingbicarbonate anions (HCO₃), acetate anions (CH₃COO), citrate, andpotassium ions (K⁺).

In a 34^(th) aspect according to the previous aspects, the control unitis configured to calculate the offset contribution term as a function ofat least one flow rate, in particular the dialysate flow rate at theoutlet of the secondary chamber (4).

In a 35^(th) aspect according to the previous aspects, the control unitis configured to calculate the offset contribution term as a function ofat least an efficiency parameter of the filtration unit (2), inparticular a clearance of the filtration unit (2), optionally the ureaclearance.

In a 36^(th) aspect according to the previous aspects, the control unitis configured to calculate the offset contribution term as a function ofat least a ratio between one flow rate, in particular the dialysate flowrate at the outlet of the secondary chamber (4), and an efficiencyparameter of the filtration unit (2), in particular a clearance of thefiltration unit (2), optionally the urea clearance.

In a 37^(th) aspect according to the previous aspects, the control unitis configured to calculate the offset contribution term as an algebraicsum of at least two, and particularly three or four or five, components,a component being function of at least a ratio between one flow rate, inparticular the dialysate flow rate at the outlet of the secondarychamber (4), and an efficiency parameter of the filtration unit (2), inparticular a clearance of the filtration unit (2), optionally the ureaclearance.

In a 38^(th) aspect according to the previous aspects, the control unit(12) is programmed for calculating said first parameter value.

In a 39^(th) aspect according to the previous aspects, the control unit(12) is programmed for receiving as an external input said firstparameter value.

In a 40^(th) aspect according to the previous aspects, the control unit(12) is programmed for storing in a memory (46) said first parametervalue, said first parameter value being not calculated by the controlunit.

In a 41^(st) aspect according to the previous aspects, the offsetcontribution term has a negative value.

In a 42^(nd) aspect according to the previous aspects, the offsetcontribution term is a function of a rest term (K_(rest)), said restterm being a conductivity contribution from lesser solutes, inparticular said lesser solutes being different from sodium, potassium,bicarbonate, and acetate, optionally said lesser solutes being differentfrom sodium, potassium, citrate, bicarbonate, and acetate.

In a 43^(rd) aspect according to the previous aspects, the offsetcontribution term is:

$c_{{di},{Na},{offset}} = {{- \frac{1}{M_{\kappa,{NaCl}}}}*\left\lbrack {{\left( {M_{\kappa,{NaHCO}_{3}} - M_{\kappa,{NaCl}}} \right)*\left( {{\alpha^{- 1}*c_{{pw},{HCO}_{3}}} - c_{d,{HCO}_{3}}} \right)} + {M_{\kappa,{KCl}}*\left( {{\alpha*c_{{pw},K}} - c_{d,K}} \right)} + {\left( {M_{\kappa,{NaAc}} - k} \right)*\left( {{\alpha^{- 1}*c_{{pw},{Ac}}} - c_{d,{Ac}}} \right)}} \right\rbrack}$

wherein:

c_(di, Na, offset) is the offset contribution term M_(κ, NaHCO) ₃ is themolar conductivity of sodium bicarbonate (NaHCO₃) M_(κ, NaCl) is themolar conductivity of sodium chloride (NaCl) M_(κ, NaAc) is the molarconductivity of sodium acetate (NaCH₃COO) M_(κ, KCl) is the molarconductivity of potassium chloride (KCl) c_(d, HCO) ₃ is the dialysisfluid concentration of bicarbonate (HCO₃ ⁻) c_(d, K) is the dialysisfluid concentration of potassium (K⁺) c_(d, Ac) is the dialysis fluidconcentration of acetate (CH₃COO⁻) c_(pw, HCO) ₃ is the estimated ormeasured pre-dialysis concentration of bicarbonate (HCO₃ ⁻) in plasmawater c_(pw, Ac) is the estimated or measured pre-dialysis concentrationof acetate (CH₃COO⁻) in plasma water c_(pw, K) is the estimated ormeasured pre-dialysis concentration of potassium (K⁺) in plasma water αis the Donnan effect corrective factor

In a 44^(th) aspect according to the previous aspects 1^(st) to 42^(nd),the offset contribution term is:

$c_{{di},{Na},{offset}} = {{- \frac{1}{M_{\kappa,{NaCl}}}}*\left\lbrack {{\left( {M_{\kappa,{NaHCO}_{3}} - M_{\kappa,{NaCl}}} \right)*\left( {{\alpha^{- 1}*c_{{pw},{HCO}_{3}}} - c_{d,{HCO}_{3}}} \right)} + {M_{\kappa,{KCl}}*\left( {{\alpha*c_{{pw},K}} - c_{d,K}} \right)} + {\left( {M_{\kappa,{NaAc}} - M_{\kappa,{NaCl}}} \right)*\left( {{\alpha^{- 1}*c_{{pw},{Ac}}} - c_{d,{Ac}}} \right)} + {\frac{Q_{do}}{K_{u}}*\left( K_{{rest}\; 1} \right)}} \right\rbrack}$

wherein:

c_(di, Na, offset) is the offset contribution term M_(κ, NaHCO) ₃ is themolar conductivity of sodium bicarbonate (NaHCO₃) M_(κ, NaCl) is themolar conductivity of sodium chloride (NaCl) M_(κ, NaAc) is the molarconductivity of sodium acetate (NaCH₃COO) M_(κ, KCl) is the molarconductivity of potassium chloride (KCl) κ_(rest1) is the conductivitycontribution from lesser solutes c_(d, HCO) ₃ is the dialysis fluidconcentration of bicarbonate (HCO₃ ⁻) c_(d, K) is the dialysis fluidconcentration of potassium (K⁺) c_(d, Ac) is the dialysis fluidconcentration of acetate (CH₃COO⁻) c_(pw, HCO) ₃ is the estimated ormeasured pre-dialysis concentration of bicarbonate (HCO₃ ⁻) in plasmawater c_(pw, Ac) is the estimated or measured pre-dialysis concentrationof acetate (CH₃COO⁻) in plasma water c_(pw, K) is the estimated ormeasured pre-dialysis concentration of potassium (K⁺) in plasma waterQ_(do) is the Dialysate flow rate at filtration unit outlet K_(u) is thefiltration unit clearance for urea α is the Donnan effect correctivefactor

In a 45^(th) aspect according to the previous aspects 1^(st) to 42^(nd),the offset contribution term is:

$c_{{di},{Na},{offset}} = {{- \frac{1}{M_{\kappa,{NaCl}}}}*\left\lbrack {{\left( {M_{\kappa,{NaHCO}_{3}} - M_{\kappa,{NaCl}}} \right)*\left( {{\alpha^{- 1}*c_{{pw},{HCO}_{3}}} - c_{d,{HCO}_{3}}} \right)} + {M_{\kappa,{KCl}}*\left( {{\alpha*c_{{pw},K}} - c_{d,K}} \right)} + {\left( {M_{\kappa,{NaAc}} - M_{\kappa,{NaCl}}} \right)*\left( {{\alpha^{- 1}*c_{{pw},{Ac}}} - c_{d,{Ac}}} \right)} + {\frac{K_{b_{Cit}}}{K_{u}}\left( {M_{\kappa_{{Na}_{3}{Cit}}} - {3M_{\kappa_{NaCl}}}} \right){\left( {{\left( {{0.167\; \alpha^{- 3}} + {0.125\; \alpha^{- 2}} + {0.706\; \alpha^{- 1}}} \right)*c_{{pw},{{Na}_{3}{Cit}}}} - c_{d,{{Na}_{3}{Cit}}}} \right)++}\frac{Q_{do}}{K_{u}}*\left( \kappa_{{rest}\; 1} \right)}} \right\rbrack}$

wherein:

c_(di, Na, offset) is the offset contribution term M_(κ, NaHCO) ₃ is themolar conductivity of sodium bicarbonate (NaHCO₃) M_(κ, NaCl) is themolar conductivity of sodium chloride (NaCl) M_(κ, NaAc) is the molarconductivity of sodium acetate (NaCH₃COO) M_(κ, Kcl) is the molarconductivity of potassium chloride (KCl) M_(κ, Na) ₃ _(Cit) Molarconductivity of trisodium citrate (Na₃C₆H₅O₇) κ_(rest1) is theconductivity contribution from lesser solutes c_(d, HCO) ₃ is thedialysis fluid concentration of bicarbonate c_(d, K) is the dialysisfluid concentration of potassium c_(d, Ac) is the dialysis fluidconcentration of acetate c_(d, Na) ₃ _(Cit) Dialysis fluid concentrationof total citrate c_(pw, HCO) ₃ is the estimated or measured pre-dialysisconcentration of bicarbonate (HCO₃ ⁻) in plasma water c_(pw, Ac) is theestimated or measured pre-dialysis concentration of acetate (CH₃COO⁻) inplasma water c_(pw, K) is the estimated or measured pre-dialysisconcentration of potassium (K⁺) in plasma water C_(pw, Na) ₃ _(Cit) isthe estimated or measured pre-dialysis concentration of total citrate inplasma water Q_(do) is the Dialysate flow rate at filtration unit outletK_(u) is the filtration unit clearance for urea K_(b) _(Cit) Filtrationunit clearance for citrate; α is the Donnan effect corrective factor

In a 46^(th) aspect according to the previous aspects, the firstparameter is a concentration of at least a substance in the dialysisfluid, said substance being in particular sodium.

In a 47^(th) aspect according to the previous aspects, the firstparameter is an isoconductive substance concentration.

In a 48^(th) aspect according to the previous aspects, the firstparameter is the plasma conductivity or the dialysis fluid conductivityin isoconductive dialysis.

In a 49^(th) aspect according to the previous aspects, the firstparameter is the plasma conductivity related parameter, said plasmaconductivity related parameter being the dialysis fluid conductivity inisoconductive dialysis.

In a 50^(th) aspect according to the previous aspects, the firstparameter is the isoconductive sodium concentration related parameter,in particular the plasma conductivity or the dialysis fluid conductivityin isoconductive dialysis.

In a 51^(st) aspect according to the previous aspects, the firstparameter is the isoconductive sodium concentration related parameter,in particular the dialysis fluid conductivity in isoconductive dialysis,and the second parameter is the sodium concentration in the blood.

In a 52^(nd) aspect according to the previous aspects, immediately aftercalculating an initial sodium concentration, the control unit isconfigured to drive the regulating means (10) to change the compositionof the dialysis fluid and to set the dialysis fluid sodium to asubstantially isoconductive sodium concentration.

In a 53^(rd) aspect according to the previous aspect, after setting thedialysis fluid sodium to a substantially isoconductive sodiumconcentration, the control unit is configured to execute a secondcalculating step, based on a second determined initial conductivity ofthe dialysate and on a second corresponding conductivity of the dialysisfluid in the dialysis supply line (8), of a second estimate of theinitial sodium concentration, said calculating the second estimate beingperformed maintaining the dialysis fluid conductivity substantiallyconstant by an isoconductive sodium concentration setting.

In a 54^(th) aspect according to the previous aspects, after calculatingthe second estimate of the isoconductive sodium concentration, thecontrol unit is configured to drive the regulating means (10) to changethe composition of the dialysis fluid and to set the dialysis fluidsodium concentration substantially equal to said second estimate.

In a 55^(th) aspect according to the previous aspects, the control unit(12) is configured to determine the conductivity of the dialysis fluidboth upstream and downstream of said filtration unit (2) for at leasttwo successively prepared dialysates with different conductivities,particularly deriving from different concentrations of sodium.

Further characteristics and advantages of the present invention willbetter emerge from the detailed description that follows of at least anembodiment of the invention, illustrated by way of non-limiting examplein the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The description will now follow, with reference to the appended FIGUREprovided by way of non-limiting example, in which:

FIG. 1 schematically represents an extracorporeal blood treatmentapparatus made according to an illustrating embodiment.

DETAILED DESCRIPTION

FIG. 1 illustrates an extracorporeal blood treatment apparatus 1 in anembodiment of the invention.

An example of a hydraulic circuit 100 is schematically illustrated, butit is to be noted that the specific structure of the hydraulic circuit100 is not relevant for the purposes of the present invention andtherefore other and different circuits to those specifically shown inFIG. 1 might be used in consequence of the functional and design needsof each single medical apparatus.

The hydraulic circuit 100 exhibits a dialysis fluid circuit 32presenting at least one dialysis fluid supply line 8, destined totransport a dialysis fluid from at least one source 14 towards atreatment station 15 where one or more filtration units 2, or dialyzers,operate.

The dialysis fluid circuit 32 further comprises at least one dialysiseffluent line 13, destined for the transport of a dialysate liquid(spent dialysis fluid and liquid ultrafiltered from the blood through asemipermeable membrane 5) from the treatment station 15 towards anevacuation zone, schematically denoted by 16 in FIG. 1.

The hydraulic circuit cooperates with a blood circuit 17, alsoschematically represented in FIG. 1 in its basic component parts. Thespecific structure of the blood circuit is also not fundamental, withreference to the present invention. Thus, with reference to FIG. 1, abrief description of a possible embodiment of a blood circuit is made,which is however provided purely by way of non-limiting example.

The blood circuit 17 of FIG. 1 comprises a blood withdrawal line 6designed to remove blood from a vascular access 18 and a blood returnline 7 designed to return the treated blood to the vascular access 18.

The blood circuit 17 of FIG. 1 further comprises a primary chamber 3, orblood chamber, of the blood filtration unit 2, the secondary chamber 4of which is connected to the hydraulic circuit 100.

In greater detail, the blood withdrawal line 6 is connected at the inletof the primary chamber 3, while the blood return line 7 is connected atthe outlet of the primary chamber 3.

In turn, the dialysis supply line 8 is connected at the inlet of thesecondary chamber 4, while the dialysis effluent line 13 is connected atthe outlet of the secondary chamber 4.

The filtration unit 2, for example a dialyzer or a plasma filter or ahemofilter or a hemodiafilter, comprises, as mentioned, the two chambers3 and 4 which are separated by a semipermeable membrane 5, for exampleof the hollow-fiber type or plate type.

The blood circuit 17 may also comprise one or more air separators 19: inthe example of FIG. 1 a separator 19 is included at the blood returnline 7, upstream of a safety valve 20.

Of course other air separators may be present in the blood circuit, suchas positioned along the blood withdrawal line 6.

The safety valve 20 may be activated to close the blood return line 7when, for example, for security reasons the blood return to the vascularaccess 18 has to be halted.

The extracorporeal blood treatment apparatus 1 may also comprise one ormore blood pumps 21, for example positive displacement pumps such asperistaltic pumps; in the example of FIG. 1, a blood pump 21 is includedon the blood withdrawal line 6.

The apparatus of above-described embodiment may also comprise a userinterface 22 (e.g. a graphic user interface or GUI) and a control unit12, i.e. a programmed/programmable control unit, connected to the userinterface.

The control unit 12 may, for example, comprise one or more digitalmicroprocessor units or one or more analog units or other combinationsof analog units and digital units. Relating by way of example to amicroprocessor unit, once the unit has performed a special program (forexample a program coming from outside or directly integrated on themicroprocessor card), the unit is programmed, defining a plurality offunctional blocks which constitute means each designed to performrespective operations as better described in the following description.

In combination with one or more of the above characteristics, themedical apparatus may also comprise a closing device operating, forexample, in the blood circuit 17 and/or in the dialysis fluid circuit 32and commandable between one first operating condition, in which theclosing device allows a liquid to flow towards the filtration unit 2,and a second operative position, in which the closing device blocks thepassage of liquid towards the filtration unit 2.

In this case, the control unit 12 may be connected to the closing deviceand programmed to drive the closing device to pass from the first to thesecond operative condition, should an alarm condition have beendetected.

In FIG. 1 the closing device includes the safety valve 20 (e.g. asolenoid valve) controlled by the unit 12 as described above. Obviouslya valve of another nature, either an occlusive pump or a further memberconfigured to selectively prevent and enable fluid passage may be used.

Alternatively or additionally to the safety valve 20, the closing devicemay also comprise a bypass line 23 which connects the dialysis fluidsupply line 8 and the dialysate effluent line 13 bypassing thefiltration unit, and one or more fluid check members 24 connected to thecontrol unit 12 for selectively opening and closing the bypass line 23.The components (bypass line 23 and fluid check members 24), which may bealternative or additional to the presence of the safety valve 20 arerepresented by a broken line in FIG. 1.

The check members 24 on command of the control unit close the fluidpassage towards the treatment zone and connect the source 14 directlywith the dialysis effluent line 13 through the bypass line 23.

Again with the aim of controlling the fluid passage towards thefiltration unit 2, a dialysis fluid pump 25 and a dialysate pump 26 maybe included, located respectively on the dialysis fluid supply line 8and on the dialysate effluent line 13 and also operatively connected tothe control unit 12.

The apparatus also comprises a dialysis fluid preparation device 9 whichmay be of any known type, for example including one or more concentratesources 27, 28 and respective concentrate pumps 29, 30 for the delivery,as well as at least a conductivity sensor 35.

Of course other kinds of dialysis fluid preparation devices 9 might beequivalently used, having a single or further concentrate sources and/ora single or more pumps.

Since the dialysis apparatus may comprise various liquid sources (forexample one or more water sources, one or more concentrate sources 27,28, one or more sources 33 of disinfectant liquids) connected to thedialysis supply line 8 with respective delivery lines 36, 37 and 38, theapparatus may exhibit, at each delivery line, a respective check member(not all are shown) and, for example, comprising a valve member 31 and34 and/or an occlusive pump.

The preparation device 9 may be any known system configured for on-linepreparing dialysis fluid from water and concentrates.

The dialysis supply line 8 fluidly connects the preparation device forpreparing dialysis fluid to the filtration unit 2. The preparationdevice 9 may be, for example, the one described in the U.S. Pat. No.6,123,847 the content of which is herein incorporated by reference.

As shown, the dialysis supply line 8 connects the preparation device 9for preparing dialysis fluid to the filtration unit 2 and comprises amain line 40 whose upstream end is intended to be connected to a source14 of running water.

Delivery line/s 36/37 is/are connected to this main line 40, the freeend of which delivery line/s is/are intended to be in fluidcommunication (for example immersed) in a container/s 27, 28 for aconcentrated saline solution each containing sodium chloride and/orcalcium chloride and/or magnesium chloride and/or potassium chloride.

Concentrate pump/s 29, 30 is/are arranged in the delivery line/s 36/37in order to allow the metered mixing of water and concentrated solutionin the main line 40. The concentrate pump/s 29, 30 is/are driven on thebasis of the comparison between 1) a target conductivity value for themixture of liquids formed where the main line 40 joins the deliveryline/s 36/37, and 2) the value of the conductivity of this mixturemeasured by means of a conductivity sensor 35 arranged in the main line40 immediately downstream of the junction between the main line 40 andthe delivery line/s 36/37.

Therefore, as mentioned, the dialysis fluid may contain, for example,ions of sodium, calcium, magnesium, and potassium and the preparationdevice 9 may be configured to prepare the dialysis fluid on the basis ofa comparison between a target conductivity value and an actualconductivity value of the dialysis fluid measured by the conductivitysensor 35 of the device 9.

The preparation device 9 comprises regulating means 10, of a known type(i.e. concentrate pump/s 29, 30), which is configured to regulate theconcentration of a specific substance, in particular an ionic substance,in the dialysis liquid. Generally it is advantageous to control thesodium concentration of the dialysis fluid.

The dialysis supply line 8 forms an extension of the main line 40 of thepreparation device 9 for preparing dialysis fluid. Arranged in thisdialysis supply line, in the direction in which the liquid circulates,there are the first flow meter 41 and the dialysis fluid pump 25.

The dialysis effluent line 13 may be provided with a dialysate pump 26and a second flow meter 42. The first and second flow meters 41, 42 maybe used to control (in a known manner) the fluid balance of a patientconnected to the blood circuit 17 during a dialysis session.

A sensor 11 is provided on the dialysis effluent line 13, immediatelydownstream the filtration unit 2, to measure a parameter value of thedialysate in the dialysate effluent line.

In detail, the parameter of the dialysate, which is measured by thesensor 11 is at least one chosen in the group consisting of conductivityof the dialysate, a conductivity-related parameter of the dialysate,concentration of at least a substance in the dialysate and aconcentration-related parameter of at least a substance in thedialysate.

In detail the sensor 11 is a conductivity sensor, which is connected tothe dialysis effluent line 13, and is configured to detect conductivityvalues of the dialysate downstream of the filtration unit 2.

Alternatively (or in combination) sensor 11 may include a concentrationsensor configured for measuring the concentration of at least onesubstance in the dialysate, such as sodium concentration.

Correspondingly, sensor 35 on the dialysis fluid supply line may be nota conductivity sensor and, differently, may include a concentrationsensor configured for measuring the concentration of at least onesubstance in the dialysis fluid, such as sodium concentration.

The control unit 12 of the dialysis apparatus represented in FIG. 1 maybe connected to a (graphic) user interface 22 through which it mayreceive instructions, for example target values, such as blood flow rateQ_(b), dialysis fluid flow rate Q_(th), infusion liquid flow rateQ_(inf) (where appropriate), patient weight loss WL. The control unit 12furthermore may receive detected values by the sensors of the apparatus,such as the aforementioned flow meters 41, 42, the (e.g. conductivity)sensor 35 of the preparation device 9 and the (e.g. conductivity) sensor11 in the dialysis effluent line 13. On the basis of the instructionsreceived and the operating modes and algorithms which have beenprogrammed, the control unit 12 drives the actuators of the apparatus,such as the blood pump 21, the aforementioned dialysis fluid anddialysate pumps 25, 26, and the preparation device 9.

As already mentioned, the described embodiments are intended to benon-limiting examples. In particular the circuits of FIG. 1 should notbe interpreted as defining or limiting, as an apparatus such as in theinvention may comprise other additional or alternative components tothose described.

For example an ultrafiltration line may be included, with at least onerespective pump connected to the dialysis effluent line 13.

One or more infusion lines 39 may also be included, with respectiveinfusion pumps 43 or flow regulation valves, the infusion lines beingconnected up to the blood return line 7 and/or the blood withdrawal line6 and/or directly to the patient. The liquid sources for the infusionlines may be pre-packaged bags 44 and/or liquids prepared by theapparatus itself.

In the example of FIG. 1, an infusion line 39 is shown directlyconnected to the blood return line 7, in particular to the air separator19. The infusion line 39 may either receive infusion liquid from apre-packaged bag 44 (solid line 45 a) or from an online preparationtrough branch 45 b (dotted line).

Of course a pre-infusion line may be alternatively or additionallyprovided receiving the infusion liquid from a bag or from an onlinepreparation device.

The blood circuit of FIG. 1 is intended for double needle treatments;however, this is a non-limiting example of the blood set.

Indeed, the apparatus may be configured to perform single needletreatments, i.e. the patient is connected to the extracorporeal bloodcircuit by way of a single needle and the extracorporeal line from thepatient is then split into a withdrawal line and a return line, using,for example, an ‘Y’ connector. During single needle treatment, a bloodwithdrawal phase removing blood from patient is alternated to a bloodreturn phase in which blood is restituted to the patient.

Furthermore one or more devices for measuring specific substanceconcentrations might be implemented either (or both) in the dialysisfluid side or (and) in the blood side of the hydraulic circuit.Concentration of calcium, potassium, magnesium, bicarbonate, and/orsodium might be desired to be known.

Finally, the above-cited one or more pumps and all the other necessarytemperature, pressure and concentration sensors may operate either onthe dialysis supply line 8 and/or on the dialysis effluent line 13, inorder to adequately monitor the preparation and movement of the liquidin the hydraulic circuit.

Given the above description of a possible embodiment of extracorporealblood treatment apparatus, thereafter the specific working of theapparatus and the algorithm programming the control unit are described.

Definitions

We define the ‘dialysis fluid’ as the fluid prepared and introduced tothe second chamber (4) of the filtration unit (2), the dialyzer. Thedialysis fluid may also be denoted “fresh dialysis fluid”.

We define the ‘dialysate’ as the fluid from the outlet from the secondchamber (4) of the filtration unit (2), the dialyzer. Dialysate is thespent dialysis fluid, comprising the uremic toxins removed from theblood.

We define ‘isoconductive dialysis’, as a dialysis treatment where theconductivity of the dialysis fluid does not change pre- topost-filtration unit (2), κ_(di)=κ_(do).

We define ‘plasma conductivity’ as the conductivity of the dialysisfluid in an isoconductive dialysis.

We define ‘isoconductive substance concentration’ as the substanceconcentration in the dialysis fluid in an isoconductive dialysis.

We define ‘isoconductive sodium concentration’ as the sodiumconcentration of the dialysis fluid in an isoconductive dialysis.

In this application the term “citrate” means that the component is inform of a salt of citric acid, such as sodium, magnesium, calcium, orpotassium salt thereof. The citric acid (denoted C₆H₈O₇) is deprotonatedstepwise, therefore the “citrate” include all the different forms,citrate (denoted C₆H₅O₇ ³⁻), hydrogen citrate (denoted C₆H₆O₇ ²⁻), anddihydrogen citrate (denoted C₆H₇O⁷⁻).

The term “citrate” or “total citrate” means that the total amount ofcitric acid and any salts thereof, such as its sodium, magnesium,calcium, or potassium salt thereof.

In other terms, “total citrate” is the sum of free citrate ions andcitrate containing complexes and ion pairs.

Glossary

The following terms are consistently used throughout the equationsprovided in the following description of the detailed working of theextracorporeal blood treatment apparatus.

c_(di, Na, offset) Offset contribution term mmol/L M_(κ, NaHCO) ₃ Molarconductivity of sodium L · mS/mmol · cm bicarbonate (NaHCO₃) M_(κ, NaCl)Molar conductivity of sodium L · mS/mmol · cm chloride (NaCl)M_(κ, NaAc) Molar conductivity of sodium L · mS/mmol · cm acetate(NaCH₃COO) M_(κ, KCl) Molar conductivity of potassium L · mS/mmol · cmchloride (KCl) M_(κ, Na) ₃ _(Cit) Molar conductivity of trisodium L ·mS/mmol · cm citrate (Na₃C₆H₅O₇) κ_(rest1) Conductivity contributionfrom mS/cm lesser solutes c_(d, HCO) ₃ Dialysis fluid concentration ofmmol/L bicarbonate (HCO₃ ⁻) c_(d, K) Dialysis fluid concentration ofmmol/L potassium (K⁺) c_(d, Ac) Dialysis fluid concentration of mmol/Lacetate (CH₃COO⁻) c_(d, Na) ₃ _(Cit) Dialysis fluid concentration ofmmol/L total citrate c_(pw, HCO) ₃ Estimated or measured pre-dialysismmol/L concentration of bicarbonate (HCO₃ ⁻) in plasma water c_(pw, Ac)Estimated or measured pre-dialysis mmol/L concentration of acetate(CH₃COO⁻) in plasma water c_(pw, K) Estimated or measured pre-dialysismmol/L concentration of potassium (K⁺) in plasma water c_(pw, Na) ₃_(Cit) Estimated or measured or known pre- mmol/L dialysis concentrationof total citrate in plasma water Q_(do) Dialysate flow rate atfiltration mL/min unit outlet Q_(Bset) Set blood flow rate mL/min K_(u)Filtration unit clearance for urea mL/min K_(b, Cit) Filtration unitclearance for mL/min citrate α Donnan effect corrective factorDimensionless κ_(di) Conductivity of the dialysis fluid mS/cm upstreamof the filtration unit κ_(do) Conductivity of the dialysis fluid mS/cmdownstream of the filtration unit (dialysate) D Dialysance of thefiltration unit mL/min Q_(d) Flow rate of the dialysis liquid mL/minκ_(p, 1) Plasma conductivity first estimate mS/cm κ_(0, di) Dialysisfluid conductivity at the mS/cm filtration unit inlet for a pureelectrolyte solution κ_(0, do) Dialysate conductivity at the mS/cmfiltration unit outlet for a pure electrolyte solution f_(pw) Plasmawater fraction, i.e., the Dimensionless part of plasma that is purewater C_(di, Na, isocond) Isoconductive sodium concentration mmol/Lκ_(j) Partial conductivity for salt j mS/cm C Concentrations mmol/Lc_(p, Na) Plasma sodium concentration mmol/L c_(pw, Na) Concentration ofsodium (Na⁺) in mmol/L plasma water c_(pw) Plasma water concentrationmmol/L c_(d) Dialysis fluid concentration mmol/L c_(di, Na) Dialysisfluid concentration of mmol/L sodium at the filtration unit inletc_(do, Na) Dialysis fluid concentration of mmol/L sodium at thefiltration unit outlet

The Donnan factor adjusts for electrical effects on ions assuringelectroneutrality to be kept over the membrane. For estimating theDonnan factor reference is made to Trans Am Soc Artif Intern Organs,1983; 29; 684-7, “Sodium Fluxes during hemodialysis”, Lauer A.,Belledonne M., Saccaggi A., Glabman S., Bosch J.

In order to implement a method for estimation of plasma sodium duringhemodialysis a model of ion transport in the filtration unit has beendeveloped. Indeed, if the blood values of some electrolytes are known orestimated, the plasma sodium may be calculated from the conductivitymeasurements by a simple filtration unit model.

According to the developed method a term, named C_(di,Na,isocond), isthe dialysis fluid isoconductive sodium concentration and a term, namedC_(di,Na,offset), is a term to obtain the plasma sodium concentration.

For two dialysis fluid separate settings (e.g. different conductivityand/or concentration of at least one solute), denoted with indices 1 and2, the first term can be calculated by the expression:

$\begin{matrix}{c_{{di},{Na},{isocond}} = \frac{{c_{{di},{Na},1}*\left( {\kappa_{{do},2} - \kappa_{{di},2}} \right)} - {c_{{di},{Na},2}*\left( {\kappa_{{do},1} - \kappa_{{di},1}} \right)}}{\left( {\kappa_{{do},2} - \kappa_{{di},2}} \right) - \left( {\kappa_{{do},1} - \kappa_{{di},1}} \right)}} & (I)\end{matrix}$

The term to obtain the plasma sodium concentration can be calculatedthrough the expression:

$\begin{matrix}{c_{{di},{Na},{offset}} = {{- \frac{1}{M_{\kappa,{NaCl}}}}*\left\lbrack {{\left( {M_{\kappa,{NaHCO}_{3}} - M_{\kappa,{NaCl}}} \right)*\left( {{\alpha^{- 1}*c_{{pw},{HCO}_{3}}} - c_{d,{HCO}_{3}}} \right)} + {M_{\kappa,{KCl}}*\left( {{\alpha*c_{{pw},K}} - c_{d,K}} \right)} + {\left( {M_{\kappa,{NaAc}} - M_{\kappa,{NaCl}}} \right)*\left( {{\alpha^{- 1}*c_{{pw},{Ac}}} - c_{d,{Ac}}} \right)}} \right\rbrack}} & ({II})\end{matrix}$

The plasma sodium relates to plasma water as:

C _(p,Na) =f _(pw) *c _(pw,Na)

where the plasma water fraction (f_(pw)) is usually about 0.93:f_(pw)≈0.93

In view of the above calculations, it derives that:

$\begin{matrix}{c_{p,{Na}} = {\frac{f_{pw}}{\alpha}*\left( {c_{{di},{Na},{isocond}} + c_{{di},{Na},{offset}}} \right)}} & ({IV})\end{matrix}$

Solution Proposal

The above described model is extremely useful in determining the bloodparameter of interest. Various steps of the proposed method which willbe described below are intended to be performed by the control unit 12of the extracorporeal blood treatment device 1, even if not explicitlystated.

In particular a treatment session is started, preferably, but notnecessarily, as a double needle hemodialysis treatment.

The user shall input the prescription values through the user interface22. For example the set values for total weight loss WL and totaltreatment time T are provided, as well as the blood flow rate Q_(b) andthe fresh dialysis flow rate Q_(di).

Other parameters may be entered through the user interface, such as bagtype, sodium user limits, etc.

The operator has to further input the ‘bicarbonate’ set before startingthe treatment.

The control unit 12 receives from the prescription or, alternatively,calculates either the initial dialysis liquid conductivity or theinitial concentration of at least one solute, e.g. sodium, in thedialysis liquid.

In this respect it is worth to note that, in the following detaileddescription, reference is made to regulating means controllingconcentration of an ionic substance, in detail sodium concentration, inthe preparation of the dialysis fluid so as to obtain a desiredconductivity of the dialysis fluid.

However, regulating means directly regulating the overall dialysis fluidconductivity is also included in the spirit of the present descriptionor, alternatively, regulating means modifying the concentration of adifferent ionic substance is included in the present description, too.

The hemodialysis or hemodiafiltration treatment is thereafter started.

The isoconductive sodium concentration is provided to the control unit12. In more detail, the isoconductive sodium concentration may becalculated according expression I.

Alternatively, an isoconductive sodium concentration related parametermay be provided to the control unit 12; the isoconductive sodiumconcentration related parameter may be the plasma conductivity. Indeedthe isoconductive sodium concentration is correlated to the plasmaconductivity; it is possible to derive, in a manner known to the personskilled in the art, the isoconductive sodium concentration knowing theplasma conductivity and vice versa; of course the composition of thedialysis fluid should be known. Indeed, the conductivity of a solutionmay be calculated as a sum of terms; each term represents a saltcontained in the solution and each term is constructed as the product ofthe molar conductivity and concentration of the salt. The concentrationof sodium may be calculated from conductivity from the same relation. Insuch a case the plasma conductivity (subsequently used to obtain theisoconductive sodium concentration) may be calculated by conventionalmethods, for example according to anyone of the methods according toEP547025, U.S. Pat. No. 5,100,554, EP658352, EP920877 or EP1108438.

To calculate the isoconductive sodium concentration (or theisoconductive sodium concentration related parameter) the conductivityupstream and downstream the filtration unit is measured for the flowingdialysis fluid.

Then an adjusted dialysis fluid having a different concentration of asolute, e.g. sodium, is prepared and the conductivity upstream anddownstream the filtration unit is measured again for the adjusteddialysis fluid; for example the two dialysis fluids may differ of about10 mmol/L.

In other terms, the basic principle of the above described monitoringsystems is the continuous measurement of the outlet dialysateconductivity when the inlet dialysate conductivity is changed forexample 1 mS/cm during, for example, two (or more) minutes.

Alternatively, the control unit 12 directly receives as an input theisoconductive sodium concentration or plasma conductivity. For example,the physician or the nurse may receive a lab analysis and may providethe datum to the machine through the user interface of the dialysismonitor; the control unit 12 is programmed for storing in a memory 46the isoconductive sodium concentration or the plasma conductivity to beused for the following dialysis fluid parameter regulation.

In addition, the isoconductive sodium concentration or the plasmaconductivity may be estimated using different formulas, not explicitlyrequiring two dialysis fluids at different sodium concentrations.

For example, according to a further embodiment, the control unit isprogrammed to calculate the initial plasma conductivity based on the sumof at least the initial conductivity of the dialysate plus a differencebetween inlet and outlet conductivity at the filtration unit, ordialyzer, weighted by a factor of the dialysate flow rate. In moredetail the difference between inlet and outlet conductivity at thefiltration unit is weighted by a factor of the blood flow rate in theblood lines too.

Specifically, according to this further embodiment, the control unit 12is configured to calculate the plasma conductivity using the followingformula:

$\begin{matrix}{\kappa_{p,1}^{\prime} = {\kappa_{0,{do}} + {\frac{Q_{do}}{Q_{Bset}}\left( {\kappa_{0,{do}} - \kappa_{0,{di}}} \right)}}} & (V)\end{matrix}$

The significance of the denotations above is given in the Glossary.

It is worth to underline that during the above described calculation ofthe initial plasma conductivity (formula (V)), the dialysis fluidcirculates through the secondary chamber 4 maintaining the dialysisfluid parameter value substantially constant.

In an additional embodiment, the control unit 12 is programmed tocalculate the initial plasma conductivity based on the sum of at leastthe initial conductivity of the fresh dialysis fluid plus a differencebetween inlet and outlet conductivity at the filtration unit weighted bya factor of the dialysate flow rate. In more detail the differencebetween inlet and outlet conductivity at the filtration unit, ordialyzer, is weighted by a factor of the filtration unit clearance too.

Specifically, according to the additional embodiment, the control unit12 is configured to calculate the plasma conductivity using thefollowing formula:

$\begin{matrix}{\kappa_{p,1}^{''} = {\kappa_{0,{di}} + {\frac{Q_{do}}{K_{u}}\left( {\kappa_{0,{do}} - \kappa_{0,{di}}} \right)}}} & ({VI})\end{matrix}$

The significance of the denotations and constants above is given in theGlossary.

It is worth to underline that during the above described calculation ofthe initial plasma conductivity (formula (VI)), the dialysis fluidcirculates through the secondary chamber 4 maintaining the dialysisfluid parameter value substantially constant.

In more detail, in the formulas above K_(u) is the dialyzer diffusiveclearance for urea. Different estimates may be used which are known tothe skilled person. K_(u) may be approximated as Q_(di)/2, for example.

Of course, both formulas (V) and (VI) for estimation of plasmaconductivity may be iteratively applied, meaning that the newlycalculated estimate of PC (k_(p,1)) is imposed to the dialysis fluid anda new estimate again calculated after taking measures of theconductivity at the inlet and outlet of the filter as soon as stableconditions are reached.

As previously mentioned, according to an innovative aspect, the controlunit 12 receives a value of a parameter. The parameter may be theisoconductive sodium concentration or the isoconductive sodiumconcentration related parameter.

As mentioned, the control unit 12 is configured for calculating thevalue of a second parameter of the blood.

The second parameter is chosen between a concentration of a substance inthe blood and a concentration-related parameter of a substance in theblood.

Depending on the specific need, the sodium content (or the content of adifferent electrolyte) in the blood may be determined.

The step of calculating the value of the second parameter of the bloodis performed as a function of a main contribution term based on/functionof the isoconductive sodium concentration and as a function of an offsetcontribution term, i.e. a term which takes into account the transportdriving gradient of certain specific substances.

The main contribution term may affect (may contribute to) the sodiumconcentration for at least 80% of the same parameter value (and inparticular for at least 90% of the parameter value), i.e. the generalvalue of the sodium concentration in plasma mainly depend onisoconductive sodium concentration.

In more detail, the offset contribution term may contribute to thesodium concentration in blood for less than 20% (or even less than 15%)of the same parameter value (and in particular for less than 10% of theparameter value).

The calculation is a weighted algebraic sum of at least the maincontribution term (c_(di,Na,isocond)) and the offset contribution term(C_(di,Na,offset)) according to the following general formula:

$\begin{matrix}{c_{p,{Na}} = {\frac{f_{pw}}{\alpha}*\left( {c_{{di},{Na},{isocond}} + c_{{di},{Na},{offset}}} \right)}} & ({VII})\end{matrix}$

In order to estimate the blood sodium content, i.e. c_(p,Na), an offsetfactor C_(di,Na,offset), needs to be applied to the isoconductive sodiumconcentration, i.e. C_(di,Na,isocond).

The main contribution term (C_(di,Na,isocond)) is a concentration valuewhich, if used as a dialysis fluid concentration of sodium would run anisoconductive dialysis; we define ‘isoconductive dialysis’, as adialysis treatment where the conductivity of the dialysis fluid does notchange pre- to post-filtration unit 2, κ_(di)=κ_(do).

As clear form formula (VII) the concentration of plasma sodium is aweighted sum of C_(di,Na,isocond) and C_(di,Na,offset). In particularthe algebraic sum of the two terms is multiplied by a factor f_(pw)/α,i.e. the plasma water fraction divided by the Donnan factor.

Though not essential since a calculation may be made based onconductivities too, the main contribution term and the offsetcontribution term are dimensionally concentrations of a substance (e.g.sodium) in a fluid.

The Applicant has understood that certain specific substances present inthe dialysis fluid, namely bicarbonate, potassium, acetate, and citratehave a major effect which should be taken into account when it isdesired to estimate the blood sodium content from a measure ofisoconductive sodium concentration. Of course other substances play arole, such as lactate, magnesium, and calcium.

Furthermore, the difference in concentration between same substances inthe blood and in the dialysis fluid influences, as well, the mentionedestimation.

Given the above, the Applicant also realized that in calculating theoffset contribution term, certain parameters having a weight indetermining the overload of sodium are known and depends on the machinedressing (e.g. used concentrates) or on the prescription for the patient(e.g. dialysate flow rate). Other parameters depend on the patientundergoing the treatment and therefore may be either directly measured(e.g. lab analysis) or estimated (e.g. based on large population numbersor patient history).

The offset contribution term assumes, in all or almost all prevailingdialysis settings, a negative value, i.e. reduces the main contributionterm, this latter being a concentration value which if used asconcentration of sodium in the dialysis fluid would allow anisoconductive treatment.

Indeed, the main contribution term takes into consideration the effectof all the ions in causing the isoconductive sodium concentration; theoffset contribution term modify this value to determine the sodium (oranother substance) concentration only.

In more detail, the control unit is configured to calculate the offsetcontribution term based on a concentration of at least a substance inthe dialysis fluid chosen in the group including bicarbonate, potassium,acetate, lactate, and citrate; in particular calculation is made as afunction of the concentration of at least two of said substances, and infurther detail as a function of the concentration of bicarbonate,potassium, acetate, and/or citrate, and lactate in the dialysis fluid.

As mentioned, the control unit is configured to calculate the offsetcontribution term as a function of the weighted difference inconcentration of at least one of the above cited substances in thedialysis fluid and the same substances in the blood plasma.

Additionally, the control unit calculates the offset contribution termas a function of the molar conductivities of at least a substance in thedialysis fluid; in detail the substance may be chosen in the groupincluding acids or salts of bicarbonate, chloride, acetate, citrate,phosphate, and sulphate, wherein the salt is formed with sodium,potassium, calcium, and magnesium.

In more detail, the calculations take into account the molarconductivities of at least two of said substances, specifically of atleast three and particularly of sodium bicarbonate (NaHCO₃), sodiumchloride (NaCl), sodium acetate (NaCH₃COO), trisodium citrate(Na₃C₆H₅O₇), and potassium chloride (KCl).

Again, the offset contribution term is a function of the differencesbetween two molar conductivities, a first molar conductivity of asubstance chosen in the group including sodium bicarbonate (NaHCO₃),sodium acetate (NaCH₃COO), trisodium citrate (Na₃C₆H₅O₇), and potassiumchloride (KCl), and a molar conductivity of sodium chloride (NaCl).

Alternatively, the offset contribution term is a function of thedifferences between two molar conductivities, a first molar conductivityof a substance chosen in the group including sodium bicarbonate(NaHCO₃), trisodium citrate (Na₃C₆H₅O₇), and potassium chloride (KCl),and a molar conductivity of sodium chloride (NaCl).

The control unit is also configured to calculate the offset contributionterm as a function of an estimated plasma water concentration of atleast a substance chosen in the group including bicarbonate, potassium,acetate, lactate, and citrate; in particular the calculation is madebased on the estimated plasma water concentration of at least two, threeor four of said substances; in one specific example of the presentdescription the offset contribution term is a function of the estimatedplasma water concentration of bicarbonate, potassium, and acetate. Inanother specific example citrate too is considered.

The estimated plasma water concentration of bicarbonate, potassium,citrate, and acetate is the mean pre-dialysis values of thecorresponding substance for large patient populations. The estimatedplasma water concentration of bicarbonate, potassium, citrate, andacetate may alternatively be based on other statistical prepared values,or historical values for the specific patient, or direct measurementsmade before or during the treatment.

Note that, in the specific formula, the estimated plasma waterconcentration may alternatively be adjusted by a respective (preferably,but not necessarily, fixed) adjusting factor. Numerical values can bee.g. 0.95 (α) or 1.05 (α⁻¹), but other values may be used (generallydepending on the protein content and charge of the ions).

The offset contribution term is an algebraic sum of a plurality ofcomponents, a first component being function of the difference, inparticular a weighted difference, in concentration of at least asubstance in the dialysis fluid and the same substance in the bloodplasma, the second component being function of the difference, inparticular a weighted difference, in concentration of at least a secondsubstance in the dialysis fluid and the same second substance in theblood plasma, the third component being function of the difference, inparticular a weighted difference, in concentration of at least a thirdsubstance in the dialysis fluid and the same third substance in theblood plasma.

The substance may be chosen in the group including bicarbonate anions(HCO₃ ⁻), acetate anions (CH₃COO⁻), citrate, and potassium ions (K⁺),but additionally also lactate.

The above general consideration is reflected in specific andnon-limiting implementing formulas which allow, when the isoconductivesodium concentration is known, to determine the precise sodiumconcentration in the blood.

Of course, different formulas including one or more of the generalprinciples/substances above stated may be alternatively used.

As previously mentioned, in order to estimate the sodium content inblood, i.e. c_(p,Na), an offset factor C_(di,Na,offset) needs to beapplied to the calculated isoconductive sodium concentration:

$\begin{matrix}{c_{p,{Na}} = {\frac{f_{pw}}{\alpha}*\left( {c_{{di},{Na},{isocond}} + c_{{di},{Na},{offset}}} \right)}} & ({VII})\end{matrix}$

where:

$\begin{matrix}{c_{{di},{Na},{offset}} = {{- \frac{1}{M_{\kappa,{NaCl}}}}*\left\lbrack {{\left( {M_{\kappa,{NaHCO}_{3}} - M_{\kappa,{NaCl}}} \right)*\left( {{\alpha^{- 1}*c_{{pw},{HCO}_{3}}} - c_{d,{HCO}_{3}}} \right)} + {M_{\kappa,{KCl}}*\left( {{\alpha*c_{{pw},K}} - c_{d,K}} \right)} + {\left( {M_{\kappa,{NaAc}} - M_{\kappa,{NaCl}}} \right)*\left( {{\alpha^{- 1}*c_{{pw},{Ac}}} - c_{d,{Ac}}} \right)}} \right\rbrack}} & ({II})\end{matrix}$

Alternatively, in case also the effect of other substances is to betaken into account, the offset factor may be calculated with a similarformula which includes a further term in the algebraic sum.

The further term is a fourth component in the sum depending on at leasta ratio between one flow rate, in particular the dialysate flow rate atthe outlet of the secondary chamber 4, and an efficiency parameter ofthe filtration unit 2, in particular a clearance of the filtration unit2, optionally the urea clearance.

In this case the formula would read:

$\begin{matrix}{c_{{di},{Na},{offset}} = {{- \frac{1}{M_{\kappa,{NaCl}}}}*\left\lbrack {{\left( {M_{\kappa,{NaHCO}_{3}} - M_{\kappa,{NaCl}}} \right)*\left( {{\alpha^{- 1}*c_{{pw},{HCO}_{3}}} - c_{d,{HCO}_{3}}} \right)} + {M_{\kappa,{KCl}}*\left( {{\alpha*c_{{pw},K}} - c_{d,K}} \right)} + {\left( {M_{\kappa,{NaAc}} - M_{\kappa,{NaCl}}} \right)*\left( {{\alpha^{- 1}*c_{{pw},{Ac}}} - c_{d,{Ac}}} \right)} + {\frac{Q_{do}}{K_{u}}*\left( K_{{rest}\; 1} \right)}} \right\rbrack}} & ({VIII})\end{matrix}$

Factor κ (namely, κ_(rest1)) defines the effect on the conductivity dueto other components in the dialysis fluid different from the componentsalready treated and included in the respective formula. Thus, the effectof salts containing calcium, magnesium, lactate, phosphate, and sulphatemay have upon the conductivity. The effect created by these componentsis most often small, and does not vary considerably between the dialysistreatments.

In case citrate is taken into consideration, the formula would read:

$\begin{matrix}{c_{{di},{Na},{offset}} = {{- \frac{1}{M_{\kappa,{NaCl}}}}*\left\lbrack {{\left( {M_{\kappa,{NaHCO}_{3}} - M_{\kappa,{NaCl}}} \right)*\left( {{\alpha^{- 1}*c_{{pw},{HCO}_{3}}} - c_{d,{HCO}_{3}}} \right)} + {M_{\kappa,{KCl}}*\left( {{\alpha*c_{{pw},K}} - c_{d,K}} \right)} + {\left( {M_{\kappa,{NaAc}} - M_{\kappa,{NaCl}}} \right)*\left( {{\alpha^{- 1}*c_{{pw},{Ac}}} - c_{d,{Ac}}} \right)} + {\frac{K_{b_{Cit}}}{K_{u}}\left( {M_{\kappa_{{Na}_{3}{Cit}}} - {3M_{\kappa_{NaCl}}}} \right){\left( {{\left( {{0.167\; \alpha^{- 3}} + {0.125\; \alpha^{- 2}} + {0.706\; \alpha^{- 1}}} \right)*c_{{pw},{{Na}_{3}{Cit}}}} - c_{d,{{Na}_{3}{Cit}}}} \right)++}\frac{Q_{do}}{K_{u}}*\left( \kappa_{{rest}\; 1} \right)}} \right\rbrack}} & ({IX})\end{matrix}$

K_(b) _(cit) is the approximated clearance value for citrate. Thisclearance may be calculated for the actual flow rates using a masstransfer value of K₀A_(cit)=0,212*K₀A_(Urea) in the corresponding K_(u)formula known to the skilled man.

Once the sodium concentration in blood is calculated, the control unitmay drive the regulating means 10 for regulating the conductivity or theconcentration of the substance in the fresh dialysis fluid and sets thethird parameter value for the dialysis fluid in the dialysis fluidsupply line 8 at a calculated set point based on the estimated bloodsodium content. The third parameter may be the sodium concentration inthe dialysis fluid or the conductivity or the same dialysis fluid.

Of course, the estimated blood sodium content may also be used to createa sodium profile in time to be applied to the specific patient in orderto control the sodium balance throughout the dialysis treatment.

1-15. (canceled)
 16. An apparatus for extracorporeal blood treatmentcomprising: a filtration unit having a primary chamber and a secondarychamber separated by a semi-permeable membrane; a blood withdrawal linein fluid communication with an inlet of the primary chamber; a bloodreturn line in fluid communication with an outlet of the primarychamber, the blood lines being configured for connection to a patientcardiovascular system; a dialysis supply line in fluid communicationwith an inlet of the secondary chamber; a dialysis effluent line influid communication with an outlet of the secondary chamber; and acontrol unit programmed for receiving a first parameter representativeof an isoconductive dialysis, the first parameter chosen from a groupincluding: (i) a concentration of a substance; (ii) aconcentration-related parameter of the substance; and (iii) aconductivity or conductivity-related parameter, wherein the control unitis configured to: calculate a second parameter, the second parameterbeing a concentration or concentration-related parameter of a substancein blood, as a function of a main contribution term based on the firstparameter and as a function of an offset contribution term based on aconcentration of at least a substance in the dialysis fluid, thesubstance chosen from a group including bicarbonate, potassium, acetate,lactate, citrate, magnesium, calcium, sulphate, and phosphate; and storethe second parameter in a memory in communication with the control unit.17. The apparatus according to claim 16, wherein the control unit isconfigured to calculate the offset contribution term based on theconcentration of two or more substances in the dialysis fluid chosenfrom a group including bicarbonate, potassium, acetate, lactate,citrate, magnesium, calcium, sulphate, and phosphate.
 18. The apparatusaccording to claim 16, wherein the control unit is configured tocalculate the offset contribution term as a function of a difference inconcentration of at least a substance in the dialysis fluid and the samesubstance in the blood, the substance chosen from a group includingbicarbonate, potassium, acetate, lactate, and citrate.
 19. The apparatusaccording to claim 16, wherein the control unit is configured tocalculate the offset contribution term as a function of a weighteddifference in concentration of at least two substances in the dialysisfluid and the corresponding same substances in the blood, the substancesbeing chosen from a group including bicarbonate, potassium, acetate,lactate, and citrate.
 20. The apparatus according to claim 16, whereinthe first parameter is an isoconductive sodium concentration orisoconductive sodium concentration-related parameter and the secondparameter is the concentration of sodium in the blood.
 21. The apparatusaccording to claim 16, wherein the main contribution term is aconcentration value which when used as a dialysis fluid concentration ofsodium performs an isoconductive dialysis.
 22. The apparatus accordingto claim 16, wherein the main contribution term affects at least 80% ofthe second parameter, and the offset contribution term contributes toless than 20% of the second parameter, and wherein calculating thesecond parameter as a function of the main contribution term and theoffset contribution term is a sub-step of calculating an algebraic sumof at least the main contribution term and the offset contribution term,wherein the offset contribution term is dimensionally a concentration ofa substance in a fluid.
 23. The apparatus according to claim 16, furtherincluding a preparation device for preparing dialysis fluid connected tothe dialysis supply line and comprising a regulating device forregulating a composition of the dialysis fluid, the regulating deviceoperated by the control unit.
 24. The apparatus according to claim 23,wherein the control unit is configured to set a third parameter for thedialysis fluid in the dialysis supply line at a set point based on thesecond parameter, the third parameter chosen from a group including (i)a conductivity of the dialysis fluid, (ii) a conductivity-relatedparameter of the dialysis fluid, (iii) a concentration of at least asubstance in the dialysis fluid, and (iv) a concentration-relatedparameter of at least a substance in the dialysis fluid, wherein thecontrol unit drives the regulating device for regulating theconductivity of the dialysis fluid or the concentration of at least thesubstance in the dialysis fluid at the set point.
 25. The apparatusaccording to claim 23, wherein the control unit is configured todetermine a time profile for a third parameter for the dialysis fluid inthe dialysis supply line, the third parameter of the dialysis fluidbeing chosen from a group including (i) a conductivity of the dialysisfluid, (ii) a conductivity-related parameter of the dialysis fluid,(iii) a concentration of at least a substance in the dialysis fluid, and(iv) a concentration-related parameter of at least a substance in thedialysis fluid, wherein the control unit drives the regulating devicefor regulating the conductivity or the concentration of at least thesubstance in the dialysis fluid, the time profile for the thirdparameter being based on the second parameter.
 26. The apparatusaccording to claim 16, wherein the control unit is configured tocalculate the offset contribution term as a function of molarconductivities of one or more substances in the dialysis fluid chosenfrom a group including sodium bicarbonate (NaHCO₃), sodium chloride(NaCl), sodium acetate (NaCH₃COO), potassium chloride (KCl), sodiumlactate (NaC₃H₅O₃), and trisodium citrate (Na₃C₆H₅O₇).
 27. The apparatusaccording to claim 16, wherein the control unit is configured tocalculate the offset contribution term as a function of a differencebetween a first molar conductivity of a substance chosen from a groupincluding sodium bicarbonate (NaHCO₃), sodium acetate (NaCH₃COO),trisodium citrate (Na₃C₆H₅O₇), sodium lactate (NaC₃H₅O₃), potassiumchloride (KCl), and a molar conductivity of sodium chloride (NaCl). 28.The apparatus according to claim 16, wherein the control unit isconfigured to calculate the offset contribution term as a function of anestimated or measured plasma water concentration of one or moresubstance chosen from a group including bicarbonate, potassium, acetate,lactate, and citrate.
 29. The apparatus according to claim 16, whereinthe control unit is configured to calculate the offset contribution termas an algebraic sum of at least two components, a first of thecomponents being a function of a concentration of at least a firstsubstance in the dialysis fluid and/or blood plasma, and a second of thecomponents being a function of a concentration of at least a secondsubstance in the dialysis fluid and/or blood plasma, wherein the firstand second substances are chosen from a group including bicarbonateanions (HCO₃ ⁻), acetate anions (CH₃COO⁻), citrate anions (C₆H₅O₇ ³⁻),and potassium ions (K⁺).
 30. The apparatus according to claim 16,wherein the control unit is configured to calculate the offsetcontribution term as an algebraic sum of at least two components, afirst of the components being a function of a weighted difference inconcentration of at least a substance in the dialysis fluid and the samesubstance in the blood plasma, the second of the components beingfunction of a weighted difference in concentration of at least a secondsubstance in the dialysis fluid and the same second substance in theblood plasma, wherein the first and second substances are chosen from agroup including bicarbonate anions (HCO₃ ⁻), acetate anions (CH₃COO⁻),citrate anions (C₆H₅O₇ ³⁻), and potassium ions (K⁺).
 31. The apparatusaccording to claim 30, wherein the control unit is configured tocalculate an isoconductive sodium concentration as a function of aconductivity of dialysis fluid upstream of the filtration unit, aconductivity of dialysis fluid downstream of the filtration unit, adialysis fluid flow rate at the inlet of the secondary chamber and anefficiency parameter of the filtration unit.
 32. The apparatus accordingto claim 31, wherein the control unit is configured to determine anisoconductive sodium concentration from at least two conductivity valuesdetermined respectively upstream and downstream of the filtration unitin at least two successively prepared dialysis fluids with differentconcentrations of sodium.